A novel mature B‐cell line (DOBIL‐6) producing both parathyroid hormone‐related protein and interleukin‐6 from a myeloma patient presenting with hypercalcaemia

Abstract

Summary.A novel human EBV-negative B-cell line, designated DOBIL-6, was established from a patient with nonsecretary myeloma. The DOBIL-6 cell has cytoplasmic g protein and expresses CD19, 20, 38, 45RO, VLA-4 and PCA-1 antigens, but lacks CD10, 45RA and VLA5 antigens. Chromosome analysis showed that DOBIL-6 cells had many complex structural abnormalities, including t(11;14) (q13;q32), which were consistent with that of the fresh tumour cells. Interestingly, abundant interleukin-6 (IL-6) and parathyroid hormone-related protein (PTHrP) accumulated in the culture supernatant of DOBIL-6 cells. Hypercalcaemia and splenomegaly associated with plasma cell proliferations which resulted in the expansion of the light zones in the follicles were observed in DOBIL-6 transplanted nude mice. RT-PCR analysis detected mRNA for PTHrP, and IL-6 as well as its receptor (GP80) in DOBIL-6 cells.Treatment of the DOBIL-6 cells with neutralizing anti-IL-6 antibody inhibited their growth in a dose-dependent manner, whereas the addition of exogenous IL-6 stimulated it in serum-depleted conditions. These findings suggest that both IL-6 and PTHrP are produced in DOBIL-6 cells, and that IL-6 promotes its growth by an autocrine mechanism. Since IL-6 is known to stimulate not only the growth of B-cell neoplasms but also osteoclastic bone resorption by cooperating with PTHrP, this simultaneous production of IL-6 and PTHrP might be synergistically linked and play a role in the development of hypercalcaemia of the patient. The DOBIL-6 cell is a useful tool to clarify the mechanism of hypercalcaemia associated with mature B-cell neoplasms.

Production of parathyroid hormone‐related protein in two new cell lines of renal cell carcinoma

“…Ohmori et al reported that treatment of the myeloma cells producing both PTHrP and IL-6 with neutralizing anti-IL-6 antibody inhibited their growth, whereas the addition of exogenous IL-6 stimulated growth. 25 A similar response was described in the human renal carcinoma cell line RC-8, which released significant amounts of PTHrP and IL-6 into the circulation after implantation into nude mice. 26 Weissglas et al suggested that IL-6 might have enhanced hypercalcemia by stimulating the tumor growth of a subpopulation of PTHrP-secreting renal carcinomas.…”

Pathogenesis of Metastatic Calcification and Acute Pancreatitis in Adult T-Cell Leukemia under Hypercalcemic State

“…Moreover, IL-2 increases PTHrP production and secretion in HTLV-1 infected T cells [59, 60]. In addition, PTHrP and IL-6 act synergistically in causing humoral hypercalcemia of malignancy [61, 62]. PTHrP is also overexpressed in ATL cells (Figure 1(f)).…”

Hypercalcemia due to sun exposure in a patient with multiple myeloma and elevated parathyroid hormone-related protein

“…Recently, the production and secretion of PTHrP by the MM cells in vitro and in vivo have been reported to occur very often (3,4,8). Simultaneous production of both IL-6 and PTHrP by a myeloma cell line has also been reported (9). The MAH caused by PTHrP is generally characterized by low normal to frankly low levels of circulating calcitriol whereas patients with primary hyperparathyroidism and a similar degree of hypercalcemia have elevated levels of 1,25-(OH) 2 D (10).…”